Biomedical subjects

A K Klein

Publications and source records attributed to A K Klein.

At least 19 recordsLinked to original sources

PubMed2001

T-Cell recovery in adults and children following umbilical cord blood transplantation.

T-cell reconstitution following allogeneic stem cell transplantation may involve thymic education of donor-derived precursors or peripheral expansion of mature T cells transferred in the graft. T cell-receptor excision circles (sjTRECs) are generated within the thymus and identify new thymic emigrants and those that have not divided. We measured quantitative and qualitative immunologic reconstitution and sjTREC levels in adult and pediatric recipients of umbilical cord blood transplants (UCBTs). sjTRECs were detected at normal levels in all children, starting 12 months after transplantation. sjTRECs were not detected until 18 months after transplantation in adults, and then only at a 3-fold lower level than expected for age. We used complementarity-determining region 3 (CDR3) spectratyping to measure changes in T cell-receptor diversity occurring with restoration of thymic function. T-cell repertoires were skewed in adults and children at 12 to 18 months after transplantation but recovered to near-normal diversity at 2 to 3 years post-UCBT. T-cell repertoires appeared more diverse earlier in children (at 1 to 2 years post-UCBT) than in adults (at 3 to 4 years post-UCBT). We conclude that early T-cell recovery after UCBT occurs primarily through peripheral expansion of adoptively transferred donor T cells and results in skewing of the T-cell repertoire. The reappearance of sjTREC-containing cells after UCBT is associated with increasing numbers of phenotypicaly naive T cells, improved mitogen and recall antigen responses, and diversification of the T-cell repertoire. The delay in central T-cell recovery in adults relative to children may be due to differences in thymic function resulting from age-related atrophy, graft-versus-host disease, or the pharmacologic effects of prophylaxis and treatment of graft-versus-host disease.

Adolescent↗

PubMed1997

Quantitative coronary angiography with deformable spline models.

Although current edge-following schemes can be very efficient in determining coronary boundaries, they may fail when the feature to be followed is disconnected (and the scheme is unable to bridge the discontinuity) or branch points exist where the best path to follow is indeterminate. In this paper, we present new deformable spline algorithms for determining vessel boundaries, and enhancing their centerline features. A bank of even and odd S-Gabor filter pairs of different orientations are convolved with vascular images in order to create an external snake energy field. Each filter pair will give maximum response to the segment of vessel having the same orientation as the filters. The resulting responses across filters of different orientations are combined to create an external energy field for snake optimization. Vessels are represented by B-Spline snakes, and are optimized on filter outputs with dynamic programming. The points of minimal constriction and the percent-diameter stenosis are determined from a computed vessel centerline. The system has been statistically validated using fixed stenosis and flexible-tube phantoms. It has also been validated on 20 coronary lesions with two independent operators, and has been tested for interoperator and intraoperator variability and reproducibility. The system has been found to be specially robust in complex images involving vessel branchings and incomplete contrast filling.

Algorithms↗

PubMed1995

Evaluation of crystalline silica as a threshold carcinogen.

The Office of Scientific Affairs within the California Department of Toxic Substances Control has reviewed the evidence on the carcinogenicity of crystalline silica. The authors consider the current evidence to be convincing to classify crystalline silica as a human carcinogen by the inhalation route. The weight of evidence for both rats and humans indicates that fibrotic and silicotic lesions in the lung result from inhalation exposure to crystalline silica and that lung cancer is secondary to those lesions in the lung. Thus crystalline silica should be considered to have a threshold for causing cancer. The critical exposure criterion is that exposure level which does not produce a fibrogenic or silicotic response; thus it is necessary to determine the no observed adverse effect level (NOAEL) for fibrogenesis. The authors recommend that the United States Environmental Protection Agency review all appropriate studies to develop a reference concentration that can be used for regulatory purposes.

Animals↗

PubMed1988

SCE induction in Chinese hamster ovary cells (CHO) exposed to G agents.

Cultured Chinese hamster ovary (CHO) cells were exposed to two neurotoxic organophosphates, either sarin (GBI, GBII) at 1.4 X 10(-3) M or soman (GD) at 1.1 and 2.2 X 10(-3) M for 1 h, grown and their metaphase chromosomes scored for sister-chromatid exchanges (SCE). No cytotoxicity was seen with either agent at any dose level tested. Since histograms of SCE per cell showed that they were non-symmetrically arrayed around the mean, the number of SCEs were analyzed by using the nonparametric tests, Mann-Whitney and Kruskall-Wallis. Agents GBI and GBII did not show any significant increase in SCE over baseline. On the other hand, GD demonstrated a statistically significant increase in SCE with and without metabolic activation. Ethyl methanesulfonate (EMS) alone at 5 X 10(-3) M and cyclophosphamide (CP) at 10(-4) M in the presence of rat microsomes (S9) induced a 3- and 8-fold increase in SCE per cell, respectively.

Animals↗

PubMed1987

The effects of in vitro exposure to the neurotoxins sarin (GB) and soman (GD) on unscheduled DNA synthesis by rat hepatocytes.

Large amounts of the nerve agents, sarin (GB) and soman (GD), are part of the military chemical arsenal and small amounts are on hand in numerous U.S. research laboratories. Thus, there is a potential for accidental occupational exposure to these compounds. As part of a study of mutagenic, reproductive and subchronic effects of these agents, we measured unscheduled DNA repair synthesis in isolated rat hepatocytes after exposure to GBI (stabilized with tributylamine), GBII (stabilized with diisopropylcarbodiimide) or GD. This was done to determine whether these agents or their metabolites directly damage DNA or their related proteins. Each agent was assayed at least once over concentrations ranging from 3.0 X 10(-4) to 2.4 X 10(-3) M for GBI and GBII and 2.3 X 10(-4) to 1.8 X 10(-3) for GD and at least 3 times at 2.4 X 10(-3) M for GBI and GBII and 1.8 X 10(-3) M for GD, added as 20% of the culture medium. In all assays, no increase in the level of DNA synthesis was observed. On the contrary, significant decreases in repair synthesis were seen in hepatocytes exposed to GBI or GBII. The decreases in DNA synthesis seen in response to GD were less marked and not significant. These observations were not related to cell death, since 8 of 10 assays performed showed no significant decrease in the amount of DNA present in cultures exposed to the nerve agents compared to the negative controls. Our results suggest that the agents GBI, GBII and GD may either inhibit the repair of DNA or protect DNA from damage.

2-Acetylaminofluorene↗

PubMed1986

Spontaneous cell-mediated cytolysis by peripheral blood cells obtained from whole-body chronically irradiated beagle dogs.

The level of natural killer (NK) activity of continuously gamma-irradiated (whole body) beagle dogs and their nonirradiated controls was studied. For analytical purposes, irradiated dogs were segregated into groups according to their clinical status: clinically normal, hypocellular, or with acute non-lymphocytic leukemia. Since unirradiated control animals exhibited a wide range of NK responses, the data from each irradiated animal were compared to its own age-matched or litter-matched unirradiated control. Of the eight clinically normal irradiated dogs (median = 146% activity of control) only one animal had a NK activity lower than that of its control. The hypocellular group (n = 5, median = 21.8% of control) and the leukemic group (n = 4, median = 52.5% of control) each contained one responder with higher activity than its control. The difference between the percentage of control of the clinically normal and clinically abnormal dogs was found to be significant (P less than 0.05). There is a negative correlation between the NK results obtained and the total accumulated dose of radiation at the time of sampling (correlation coefficient = -0.739, P less than 0.01), suggesting a radiation effect upon natural killer activity, which is evidence by enhancement at lower doses and depression at higher doses of irradiation.

Animals↗

PubMed1985

Effect of continuous, whole-body gamma irradiation upon canine lymphohematopoietic (CFU-GM, CFU-L) progenitors and a possible hematopoietic regulatory population.

Clonogenic assays for granulocytes-macrophages (CFU-GM) in bone marrow and for T lymphocytes (CFU-L) in peripheral blood were performed on dogs continuously exposed to 60Co irradiation (0.02, 0.04, or 0.11 Gy/day). When decreased numbers of CFU-GM were observed they correlated well with the clinical status of the dogs but were not generally associated with increasing cumulative doses of absorbed irradiation. In clinically normal, irradiated animals, decreased CFU-GM values and myeloid-erythroid ratios were observed, suggesting that chronic irradiation may affect the granulocytic series well before decreased peripheral blood values are seen. In hypocellular dogs the number of CFU-GM were significantly decreased compared to values obtained from control or clinically normal irradiated dogs, while virtually no CFU-GM were observed in the leukemic dogs. Only the CFU-GM values of the hypocellular group showed an association, e.g., a suggestion of an abortive regenerative effort, with increasing absorbed dose. Proliferative capacity of T lymphocytes (CFU-L) was not affected by either increasing absorbed irradiation or the presence of leukemia. D0 values were determined on marrow fibroblastic cells to ascertain whether a radioresistant subpopulation of stromal elements would result from continuous in vivo irradiation. No correlation was found between absorbed dose and increased D0 values. However, seven of eight dogs which developed acute nonlymphocytic leukemia displayed marrow fibroblastic cells with elevated D0 values. These radioresistant marrow fibroblastic cells were assayed for their ability to support normal granulopoiesis and found to be not significantly different from control fibroblasts.

Animals↗

PubMed1984

The influence of fibroblast-like cells derived from canine fetal hematopoietic tissues on the regulation of lymphohematopoiesis.

Media conditioned by fibroblast-like cells derived from organs active in fetal lymphohematopoiesis were studied for their effects on adult granulocyte/macrophage colony-forming units (CFU-GM). Fibroblasts from fetal liver produced a factor stimulatory for CFU-GM, whereas fibroblasts from fetal marrow produced a factor inhibitory for CFU-GM which was not completely relieved by adding indomethacin to the assay. Our studies indicated that neither fetal marrow nor fetal liver produced factors affecting lymphocyte colony-forming units (CFU-L). Cell-cell interactions between fibroblast-like cells derived from fetal liver or marrow and normal adult CFU-GM were also studied. We observed that fibroblasts derived from both fetal and adult marrow inhibited colony formation, whereas inhibition in the presence of fetal liver fibroblasts was minimal. Loss of inhibitory activity by a liver fibroblast cell line over repeated passages was seen. Differential analysis of colonies formed above an adherent layer of fetal marrow fibroblasts suggested that these fibroblasts suppress myeloid/macrophage differentiation to a far greater degree than did adult marrow fibroblasts. A role in the regulation of fetal lymphohematopoiesis may be played by stromal fibroblasts.

Animals↗

PubMed1984

In vitro radiation response studies on bone marrow fibroblasts (CFU-F) obtained from normal and chronically irradiated dogs.

The radiation resistance of bone marrow fibroblasts as measured by their proliferative potential was evaluated in chronically irradiated dogs. Bone marrows were obtained from eight dogs that had been chronically irradiated beginning at 21 days of gestation or after birth and eight age-matched controls. Of these irradiated dogs, four were either preleukemic or exhibited frank acute nonlymphocytic leukemia. The other four were clinically normal but demonstrated abnormalities in their marrow that could be attributed to radiation effects and/or other pathologic changes. Fibroblasts from six of the irradiated dogs were significantly more radioresistant than those of their controls. Five of these six dogs subsequently succumbed to hematopathologic disease, while the two irradiated dogs with normal fibroblasts remained clinically normal, suggesting that this observed radioresistance may be linked to the disease process.

Animals↗

PubMed1984

Increased in vitro radioresistance of bone marrow fibroblastic progenitors (CFU-F) from patients with acute non-lymphocytic leukemia.

The proliferative potential following in vitro irradiation of bone marrow fibroblastic progenitors (CFU-F) derived from four patients with acute nonlymphocytic leukemia (ANLL) and seven nonleukemic subjects was compared. The CFU-F from the ANLL patients were significantly more radioresistant than the CFU-F from the nonleukemic subjects. The increased radioresistance in ANLL patients was evident in both the mean slope of the survival curve (control = -0.385, ANLL = -0.256) and in the Do values (control = 2.68 Gy, ANLL = 4.61 Gy). Thus CFU-F derived from ANLL patients differ from those derived from nonleukemics in both radioresistance and in granulopoietic effects as suggested from previous studies.

Bone Marrow↗

PubMed1983

Characterization of canine fetal lymphohematopoiesis: studies of CFUGM, CFUL, and CFUF.

We assayed the colony forming units for granulocyte-macrophages (CFUGM), T-lymphocytes (CFUL) and fibroblasts (CFUF) in the blood, bone marrow, liver and spleen of the canine at 45 and 55 days of gestation and 4 and 30 days post partum. As the number of CFUGM per 5 x 10(5) cells increased in the fetal liver, the number of CFUGM increased in circulating blood, whereas when the number of CFUGM decreased in liver and blood, CFUGM increased in both bone marrow and spleen. This suggests that CFUGM are produced in the liver, are released into the circulation and then transported to the spleen and bone marrow. CFUF studies showed that canine fetal bone marrow and spleen are active sites of fibroblast proliferation, whereas the liver is not. Morphologic examination of colonies derived from concanavalin-A stimulated progenitors ("CFUL") demonstrated that these colonies from fetal tissues and adult bone marrow were not exclusively lymphoid but were also made up of significant numbers of precursors of the myeloid and monocytic series. Lymphocyte stimulation tests (LST) showed the presence of a large population of mitogen-independent dividing cells, suggesting that fetal lymphohematopoiesis may be at least partially under the influence of factors other than those of adult cells.

Animals↗

PubMed1981

Morphological studies on 'adherent cells' in bone marrow cultures from humans, dogs, and mice.

Comparative morphological studies were conducted on adherent cells in bone marrow cultures obtained from humans, dogs, and mice. Scanning electron micrographs demonstrated that the adherent colonies are much more homogeneous in humans and dogs and appear larger and more flattened than in mice. In mice, many more rounded cells (macrophages) were seen intermixed with the flattened cells. Transmission electron microscopy demonstrated that the flattened type of cells are characterized by a large primitive nucleus and abundant cytoplasm exhibiting an extensive network of microtubules and submembranous microfilaments and the formation of endoplasmic reticulum-associated secretory bodies. Our results would favor a fibroblastic rather than epithelial nature of the flattened cell type.

Animals↗

PubMed1978